Background: Thyroid disorders are medical condition that affects the function of the thyroid gland; however, many cases life-threatening conditions. Thyroid disorders are very common globally with had 20 million people under treatment. Radioactive iodine can kill thyroid cells and helps to get rid of any remaining thyroid tissues. Aim: The aim of this study is to evaluate the effect of designed nursing instructions on fatigue and functional status levels among patients receiving radioactive iodine therapy. Design: Quasi-experimental pretest–posttest non-equivalent control group design was utilized in the current study. Setting: The current study was conducted in the Nuclear Medicine Department of Nasser Institute for Research and Treatment Hospital in Cairo, Egypt. Sample: A 60 adult a convenient sample over a period of six consecutive months of adult male and female patients diagnosed with hyperthyroidism and receiving radioactive iodine therapy was recruited in the study. Tools: Three tools were utilized to collect data; Personal and Medical Related Data Form (PMRD), Piper Fatigue Scale (PFS) and Functional Assessment of Cancer Therapy Version four (FACT - G). Results: The study revealed that 83.3% of the study group and 93.3% of the control group are females. A statistically significant difference in fatigue level and functional status level among the study group and control group after two weeks post intervention (X2= 11.27 P=0.001), X2= 20.57 P=0.000 respectively. Conclusion: The application of the designed nursing instructions decreases fatigue level and improves functional status level among patients receiving radioactive iodine therapy. Recommendation: The application of nursing instructions for patients receiving radioactive iodine therapy is recommended to decrease fatigue level and improve functional status level.